Fatigue, Quality of Life and Metabolic Changes in Men Treated with First-line Enzalutamide versus Abiraterone Plus Prednisolone for Metastatic Castration-resistant Prostate Cancer (HEAT): A Randomised Trial Protocol - Beyond the Abstract

The hormonal therapeutic landscape for metastatic prostate cancer has changed rapidly over the past decade from ADT to several new therapies targeting the androgen axis; enzalutamide, abiraterone, apalutamide, and darolutamide. In these rapidly evolving times of new treatment options, physicians are left with a ‘billion-dollar question’: What is the best choice of treatment?  


Between treatments with similar efficacy, the choice is driven by availability, reimbursement options and to a lesser extent the physicians’ and patients’ preferences and differences in side-effects. While there are some trends towards differences in side-effect profiles between the available drugs reported in separate phase III trials, no head-to-head comparative clinical trials investigating differences in side-effect profiles, that may aid treatment choice, are available. Such trials are rarely undertaken by the industry. This task relies on the medical community.

For men with metastatic castration-resistant prostate cancer (mCRPC), the treatment choice is limited to enzalutamide or abiraterone acetate combined with prednisone (AAP).

Many men with mCRPC are already experiencing fatigue, sarcopenia and weight gain due to androgen-deprivation therapy and to some extent the cancer itself. Both enzalutamide and AAP may lead to a worsening of these symptoms, affecting quality of life.

Enzalutamide is a potent nonsteroidal antiandrogen that unlike AAP passes the blood-brain-barrier, which may increase the risk of fatigue and cognitive impairment. Importantly, fatigue has been reported as the most common or burdensome side-effect for both enzalutamide and AAP in the original phase III trials and in a comparative observational study from Vancouver.1–3 At the ASCO-GU Annual Meeting 2018, comparative results from two observational studies REEAcT and AQUARiOUS were reported, showing a difference in patient-reported fatigue favoring AAP.4,5

In contrast, AAP inhibits the CYP17A1 enzyme leading to a block of precursors (dehydroepiandrosterone and androstenedione) of testosterone. This inhibition leads to undesired physiological effects including a decrease in cortisol, which leads us to the joker of AAP treatment: prednisone. Even though the low-dose of prednisone might lead to better fatigue outcomes, recently Attard et al. reported differences in metabolic changes depending on which glucocorticoid treatment regime was used, in a randomized clinical trial. The standard AAP dose of 10 mg prednisone daily was associated with a significant decrease in total lean body mass and an increase in body fat after only 12 weeks of treatment.6 A loss of muscle strength increases the risk of falls, while a gain in fat mass increases the risk of metabolic syndrome - both unfortunate risk factors for men with mCRPC who are predisposed to osteoporosis and cardiovascular disease.

By better understanding the true differences in side-effects between these drugs, in a real world setting, a tailored treatment decision can be made based on the individual’s morbidity profile and current complaints. Thus, avoiding exacerbation of present symptoms from long exposure to ADT. The goal of prostate cancer treatment in this later stage of the disease must not only be improving overall survival but also reducing treatment induced morbidity and improving quality of life.

The Herlev Enzalutamide versus Abiraterone Trial (HEAT) is an ongoing randomized clinical trial comparing fatigue, HRQoL and metabolic changes in men with mCRPC treated with first-line enzalutamide versus AAP. The method is described in our newly published protocol article. This project is a collaboration between urologists, endocrinologists and oncologists with the aim to improve prostate cancer patient care. Results are expected to be ready in 2020.

Written by: Klara Kvorning Ternov, MD and Peter Busch Østergren, MD, PhD, Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark. @KTernov, @PeterBOstergren.

References:
  1. Salem S, Komisarenko M, Timilshina N, Martin L, Grewal R, Alibhai S, et al. Impact of Abiraterone Acetate and Enzalutamide on Symptom Burden of Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer. Clin Oncol (R Coll Radiol) [Internet]. 2017 Sep;29(9):601–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28395931
  2. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med [Internet]. 2013 Jan 10;368(2):138–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29137449
  3. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med [Internet]. 2014 Jul 31;371(5):424–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29137449
  4. Thiery Vuillemin A, Poulsen MH, Dourthe L-M, Trepiakas R, Lagneau E, Pintus EP, et al. Six-month patient-reported outcome (PRO) results from AQUARiUS, a prospective, observational, multicenter phase 4 study in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate + prednisone (AAP) or enzalutamide (ENZ). J Clin Oncol. 2018;36(15_suppl):5058–5058.
  5. Shore ND, Saltzstein DR, Sieber PR, Mehlhaff B, Gervasi L, Phillips J, et al. Real-world study of enzalutamide and abiraterone acetate (with prednisone) tolerability (REAAcT): Results. J Clin Oncol. 2018;36(6_suppl):296–296.
  6. Attard G, Merseburger AS, Arlt W, Sternberg CN, Feyerabend S, Berruti A, et al. Assessment of the Safety of Glucocorticoid Regimens in Combination with Abiraterone Acetate: A Randomized, Open-Label Phase 2 Study. JAMA Oncol. 2019
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